In recent years, the use of fluorescence spectroscopy has been explored for diagnosis of cancer. Infrared imaging (IRI) using a spectroscopic agent, has several advantages over other in vivo techniques in that the technique is non-invasive and under proper conditions can give deep penetration and quantitative results. The complete profile of uptake, retention and elimination of needed spectroscopic agents can be followed within a single laboratory animal thus reducing the number of animals required in preclinical trials.
The requirements for an ideal spectroscopic agent needed for infrared imaging techniques are as follows: i) it should preferentially localize in tumor cells; ii) it should have high fluorescent efficiency; iii) it should not produce phototoxicity or other adverse effects in a patient; iv) it should be easy to synthesize; v) it should be chemically pure; and vi) it should have a long wave length emission so that deep seated tumors can be detected.
Porphyrins, chlorins, and bacteriochlorins including their analogs and derivatives have recently found superior utility as photodynamic compounds for use in diagnosis and treatment of disease, especially certain cancers. These compounds have also found utility in treatment of psoriasis and papillomatosis.
Such derivatives include dimers and trimers of these compounds. Permissible derivatives also include ring variations of these compounds; provided that, the central sixteen sided four nitrogen heterocycle of these compounds remains intact. Chlorophyllins, purpurins and pheophorbides and their derivatives are, therefore, included within "porphyrins, chlorins, and bacteriochlorins and their derivatives and analogs". Such derivatives include modifications of substituents upon these ring structures.
Numerous articles have been written on this subject, e.g. "Use of the Chlorophyll Derivative Purpurin-18, for Synthesis of Sensitizers for Use in Photodynamic Therapy", Lee et al., J. Chem. Soc., 1993, (19) 2369-77; "Synthesis of New Bacteriochlorins And Their Antitumor Activity", Pandey et al., Biology and Med. Chem. Letters, 1992; "Photosensitizing Properties of Bacteriochlorophyllin a and Bacteriochlorin a, Two Derivatives of Bacteriochlorophyll a", Beems et al., Photochemistry and Photobiology, 1987, v. 46, 639-643; "Photoradiation Therapy. II. Cure of Animal Tumors With Hematoporphyrin and Light", Dougherty et al., Journal of the National Cancer Institute, July 1975, v. 55, 115-119; "Photodynamic therapy of C3H mouse mammary carcinoma with haematoporphyrin di-esters as sensitizers", Evensen et al., Br. J. Cancer, 1987, 55, 483-486; "Substituent Effects in Tetrapyrrole Subunit Reactivity and Pinacol-Pinacolone Rearrangements: VIC-Dihydroxychlorins and VIC-Dihydroxybacteriochlorins" Pandey et al., Tetrahedron Letters, 1992, v. 33, 7815-7818; "Photodynamic Sensitizers from Chlorophyll: Purpurin-18 and Chlorin p.sub.6 ", Hoober et al., 1988, v.48, 579-582; "Structure/Activity Relationships Among Photosensitizers Related to Pheophorbides and Bacteriopheophorbides", Pandey et al., Bioorganic and Medicinal Chemistry Letters, 1992, v 2, 491-496; "Photodynamic Therapy Mechanisms", Pandey et al., Proceedings Society of Photo-Optical Instrumentation Engineers (SPIE), 1989, v 1065, 164-174; and "Fast Atom Bombardment Mass Spectral Analyses of Photofrin II.RTM. and its Synthetic Analogs", Pandey et al., Biomedical and Environmental Mass Spectrometry, 1990, v. 19, 405-414. These articles are incorporated by reference herein as background art.
Numerous patents in this area have been applied for and granted world wide on these photodynamic compounds. Reference may be had, for example to the following U.S. patents which are incorporated herein by reference: U.S. Pat. Nos. 4,649,151; 4,866,168; 4,889,129; 4,932,934; 4,968,715; 5,002,962; 5,015,463; 5,028,621; 5,145,863; 5,198,460; 5,225,433; 5,314,905; 5,459,159; 5,498,710; and 5,591,847.
At least one of these compounds "Photofrin.RTM." has received approval for use in the United States, Canada and Japan. Others of these compounds are in clinical trials or are being considered for such trials.
The term "porphyrins, chlorins and bacteriochlorins" as used herein is intended to include their derivatives and analogs, as described above, and as described and illustrated by the foregoing articles and patents incorporated herein by reference as background art.
Such compounds have been found to have the remarkable characteristic of preferentially accumulating in tumors rather than most normal cells and organs, excepting the liver and spleen. As a result, many tumors can be detected at an early stage due to the light fluorescing nature of the compounds in the tumors. Furthermore, many such tumors can be killed because the compounds may be activated by light to become tumor toxic.
Unfortunately such compounds, as might be expected, are not without some side affects. One of the most annoying, though usually manageable, side effects is the fact that patients exposed to these compounds become sensitive to light. As a result, after treatment, a patient must restrict exposure to light, especially sun light, by remaining indoors as much as possible, by use of dark glasses and by careful use of sun screens.
It would therefore be desirable to have a photodynamic compound, as described above, which continues to be effective as a diagnostic aid, yet having reduced photosensitizing qualities.